10-69295633-G-T

Variant names:

• chr10-69295633-G-T
• rs201626997
• NM_001358263.1:c.28G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001358263.1(HK1):​c.28G>T​(p.Ala10Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,606,244 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: HK1 NM_001358263.1 missense, splice_region
• Scores: Splicing: ADA: 0.1046
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.765
• Publications: 7 publications found

Genes affected

HK1 (HGNC:4922): (hexokinase 1) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]

HK1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with visual defects and brain anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 79

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• non-spherocytic hemolytic anemia due to hexokinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 4G

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003704846).
• BP6: Variant 10-69295633-G-T is Benign according to our data. Variant chr10-69295633-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2428596.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000742 (113/152308) while in subpopulation SAS AF = 0.0214 (103/4824). AF 95% confidence interval is 0.018. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358263.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	NM_001358263.1	MANE Plus Clinical	c.28G>T	p.Ala10Ser	missense splice_region	Exon 4 of 21	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.121G>T	p.Ala41Ser	missense splice_region	Exon 6 of 23	NP_001309294.1
	HK1	NM_001322364.2		c.28G>T	p.Ala10Ser	missense splice_region	Exon 3 of 20	NP_001309293.1	P19367-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.28G>T	p.Ala10Ser	missense splice_region	Exon 4 of 21	ENSP00000494664.1	P19367-3
	HK1	ENST00000464803.6	TSL:1	c.121G>T	p.Ala41Ser	missense splice_region	Exon 6 of 7	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000480047.5	TSL:1	n.332G>T		splice_region non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00264 AC: 664 AN: 251398 AF XY: 0.00339

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00131 AC: 1909 AN: 1453936 Hom.: 36 Cov.: 28 AF XY: 0.00186 AC XY: 1344 AN XY: 723912

African (AFR) AF: 0.0000600 AC: 2 AN: 33326

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0198 AC: 1708 AN: 86094

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53386

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5742

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1104814

Other (OTH) AF: 0.00131 AC: 79 AN: 60116

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74470

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0214 AC: 103 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.15
DANN	Benign	0.56
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0036	T
MetaSVM	Uncertain	-0.082	T
PhyloP100		-0.77
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.33
ClinPred		0.027	T
GERP RS		-3.8
gMVP		0.42
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201626997; hg19: chr10-71055389;